Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma found in children and young adults. It is characterized by the expression of a number of skeletal muscle-specific proteins, including MyoD and muscle α-actin. However, unlike normal myoblasts, RMS cells differentiate poorly both in vivo and in culture. As microRNAs are known to regulate tumorigenesis, intensive efforts have been made to identify microRNAs that are involved in RMS development. In this work, we found that miR-203 was frequently down-regulated by promoter hypermethylation in both RMS cell lines and RMS biopsies and could be reactivated by DNA-demethylating agents. Re-expression of miR-203 in RMS cells inhibited their migration and proliferation and promoted terminal myogenic differentiation. Mechanistically, miR-203 exerts its tumor-suppressive effect by directly targeting p63 and leukemia inhibitory factor receptor in RMS cells, which promotes myogenic differentiation by inhibiting the Notch and the JAK1/STAT1/STAT3 pathways, respectively. Our work reveals that miR-203 functions as a tumor suppressor in RMS development.
Keywords:
DNA Methylation; JAK Kinase; Leukemia Inhibitory Factor Receptor; Muscle Differentiation; Notch; Proliferation; Rhabdomyosarcoma; miR-203; p63.
Publication types
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Clinical Trial
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Differentiation / genetics
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Cell Line, Tumor
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DNA Methylation*
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DNA, Neoplasm / genetics
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DNA, Neoplasm / metabolism*
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Down-Regulation*
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Female
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Gene Expression Regulation, Neoplastic*
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Genes, Tumor Suppressor*
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Humans
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Janus Kinase 1 / genetics
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Janus Kinase 1 / metabolism
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Male
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Mice
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Mice, Nude
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MicroRNAs / biosynthesis*
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MicroRNAs / genetics
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Promoter Regions, Genetic*
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Receptors, Notch / genetics
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Receptors, Notch / metabolism
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Receptors, OSM-LIF / genetics
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Receptors, OSM-LIF / metabolism
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Rhabdomyosarcoma / genetics
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Rhabdomyosarcoma / metabolism*
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Rhabdomyosarcoma / pathology
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STAT1 Transcription Factor / genetics
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STAT1 Transcription Factor / metabolism
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / metabolism
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Signal Transduction / genetics
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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DNA, Neoplasm
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MIRN203 microRNA, human
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MicroRNAs
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Neoplasm Proteins
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Receptors, Notch
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Receptors, OSM-LIF
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STAT1 Transcription Factor
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STAT1 protein, human
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STAT3 Transcription Factor
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STAT3 protein, human
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TP63 protein, human
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Transcription Factors
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Tumor Suppressor Proteins
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JAK1 protein, human
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Janus Kinase 1